1. health and fitness
2. disease

REVIEW
CME
CREDIT
EDUCATIONAL OBJECTIVE: Readers will consider when further evaluation of mildly abnormal liver enzyme
levels is warranted
George Aragon, MD
Center for Liver Diseases, Inova Fairfax
Hospital, Falls Church, VA; Department
of Gastroenterology, George Washington
University, Washington, DC
Zobair M. Younossi, MD, MPH
Center for Liver Diseases, Inova Fairfax Hospital,
Falls Church, VA
When and how to evaluate
mildly elevated liver enzymes
in apparently healthy patients
■ ■ABSTRACT
Because 1% to 9% of people without symptoms have
elevated liver enzymes, extensive evaluation of all abnormal test results would expose many patients to undue
risks and expenses. On the other hand, failure to evaluate minor liver enzyme elevations could mean missing
the early diagnosis of potentially treatable disorders. This
review discusses likely causes of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase levels and provides algorithms for evaluating high
liver enzyme values in apparently healthy patients in the
primary care setting.
■ ■KEY POINTS
Nonalcoholic fatty liver disease is the most common
cause of asymptomatic elevated aminotransferase levels.
Suspect alcoholic liver disease when the aminotransferases are elevated and the aspartate aminotransferase
level is two to three times higher than the alanine aminotransferase level, especially when gamma-glutamyl
transferase levels are elevated.
If medications or alcohol is a suspected cause of elevated aminotransferase levels, remeasure the levels after 6
to 8 weeks of abstinence.
doi:10.3949/ccjm.77a.09064
n seemingly healthy patients, abnormal
Iexperienced
liver enzyme levels challenge even the most
clinicians in deciding what further
evaluation to pursue, if any. Automated laboratory testing has made serum liver enzyme levels
very easy to obtain, leading to an increase in
testing and also in the number of incidental
abnormal findings. An estimated 1% to 9% of
people who have no symptoms have high liver
enzyme levels when screened with standard
biochemistry panels.1,2 A US survey2 showed
elevated alanine aminotransferase (ALT) in
8.9% of surveyed people from 1999 to 2002, an
increase from previous reports.
An extensive evaluation can be costly, anxiety-provoking, and risky, especially if it leads
to unnecessary invasive procedures such as liver
biopsy or endoscopic retrograde cholangiopancreatography (ERCP). Not all people with a
single, isolated, mildly elevated liver enzyme
value have underlying liver disease, nor do
they require an extensive evaluation. Factors
to consider when deciding whether to evaluate
include:
• The patient’s overall health, including
chronic illness
• The duration and pattern of enzyme elevation
• Patient characteristics such as age, a personal or family history of liver, lung, or
neurologic disease, risk factors for viral
hepatitis, amount of alcohol consumption,
use of prescribed or over-the-counter drugs
or dietary supplements
• The costs and risks associated with additional evaluation.
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Table 1
Liver diseases and associated
liver enzyme elevations
Nonalcoholic
fatty liver
disease
may be the
most common
cause of mildly
elevated liver
enzymes
in US patients
Hepatocellular diseases
(aminotransferase elevations predominate)
Common
Nonalcoholic fatty liver disease
Chronic viral hepatitis
Genetic hemochromatosis
(northern European ethnicity)
Alcoholic liver disease
Medication toxicity (see Table 2)
Autoimmune hepatitis
Less common
Wilson disease
Alpha-1-antitrypsin deficiency
Cholestatic diseases (alkaline phosphatase
and gamma-glutamyl transferase elevations
predominate)
Common
Primary biliary cirrhosis
Primary sclerosing cholangitis
Neoplasm
Biliary obstruction (gallstones, etc)
Drug hepatotoxicity
Less common
Autoimmune cholangiopathy
Sarcoidosis
This article reviews the most likely causes
of elevated aminotransferase, alkaline phosphatase, and gamma-glutamyl transferase
(GGT) levels. It also provides an algorithm
for evaluating mildly abnormal liver enzyme
values in apparently healthy people. Patients
with signs of hepatic decompensation need a
more concise and urgent evaluation.
■■ PATTERNS OF LIVER ENZYME ELEVATION
“Liver function test” is commonly used to
describe liver enzyme measurements, but the
term should be reserved for tests of the functional hepatic reserve—traditionally, the albumin level and the prothrombin time.3
On the other hand, elevated serum liver
enzymes (aminotransferases, alkaline phosphatase, and GGT) can reflect abnormalities
in liver cells or in the bile duct. For example,
predominant elevation of aminotransfer-
196 ases typically indicates hepatocellular injury,
whereas elevated alkaline phosphatase and
GGT indicates cholestatic injury. Elevated alkaline phosphatase and aminotransferases can
indicate a mixed pattern of injury.
High AST, ALT suggest liver cell damage
Both aspartate aminotransferase (AST) and
ALT are normally present in serum at low levels, usually less than 30 to 40 U/L. Although
the actual values may differ from laboratory to
laboratory, normal serum levels are usually less
than 40 U/L for AST and less than 50 U/L for
ALT. On the other hand, some experts have
suggested lowering the upper limit of normal
because of the increasing rate of obesity and
associated nonalcoholic fatty liver disease,
which may not be detected using the traditional, higher normal values. Acceptance is
growing for using ALT levels less than 40 U/L
in men and less than 31 U/L in women, and
AST levels less than 37 U/L in men and less
than 31 U/L in women, as normal thresholds.
Although ALT is present in several organs
and in muscle, the highest levels are in the
liver, which makes this enzyme a more specific
indicator of liver injury. Both AST and ALT
are released into the blood in greater amounts
when hepatocytes are damaged.
Alkaline phosphatase suggests cholestasis
Alkaline phosphatase comes mostly from the
liver and bone. In general, normal serum alkaline phosphatase levels in adults range between 20 and 120 U/L. When bone disease
is excluded, an elevation suggests biliary obstruction, injury to the bile duct epithelium,
or cholestasis. Additionally, there are rare cases of benign familial elevation of serum alkaline phosphatase, mainly of intestinal origin.
GGT is not specific
GGT is present in hepatocytes and biliary epithelial cells. The normal range is 0 U/L to 50
U/L in men, and 0 U/L to 35 U/L in women.
GGT elevation is the most sensitive marker
of hepatobiliary disease. However, its routine
clinical use is not recommended, as it cannot
by itself indicate a specific cause of liver disease, although measuring the GGT level can
help determine a hepatic origin for an isolated
elevation of alkaline phosphatase.
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■■ risk factors guide the workup
of ELEVATED eNZYMES
Before beginning an extensive evaluation
of an elevated liver enzyme, a brief review
of liver diseases and how they are associated
with specific liver enzyme elevations is useful
(Table 1). This information and clinical data
obtained from the history and physical examination provide important clues to guide further investigation.
Chronic viral hepatitis
Prevalence. Hepatitis C virus infection affects an estimated 1.8% of the general population, but the rate is much higher in people
with known risk factors (see below), and those
with ALT levels greater than 40 U/L.
Hepatitis B virus infection is somewhat
less common: between 0.2% and 0.9% of the
general US population have positive results
on tests for hepatitis B surface antigen. However, the prevalence of this antigen in the
United States can be as high as 20% in patients who have emigrated from endemic areas
of the world. The risk factors described below
dramatically increase the prevalence of both
viruses.
Risk factors. Risk factors include bloodproduct transfusions (especially before 1992),
intravenous drug use, intranasal cocaine use,
hemodialysis, organ transplantation, and birth
in an endemic region. Although both viruses can be transmitted sexually, hepatitis B is
more readily transmitted by this route than
hepatitis C. Worldwide, transmission of hepatitis B virus usually occurs shortly after birth or
at a young age.
Comments. Most patients with chronic
viral hepatitis have no symptoms or only
mild symptoms and minimally elevated ALT
and AST levels, ie, two to five times higher
than the upper limit of normal. Given the
relatively high prevalence of hepatitis C, serologic testing for it should be done early in
the evaluation of chronically elevated liver
enzyme levels.4,5
Hereditary hemochromatosis
Prevalence. The prevalence of the major
HFE-gene mutations that cause hereditary hemochromatosis is 0.25% to 0.5% in people of
northern European descent. In northern Europe, about 1 person in 10 is heterozygous and
1 in 200 to 400 is homozygous for the mutated
gene.
Risk factors. Northern European ancestry
is the primary risk factor. In men, the onset
of disease is usually in the third and fourth
decades of life, while menses protects women
until menopause. From 83% to 85% of people
with clinically defined hemochromatosis are
homozygous for the C282Y mutation in the
HFE gene.
Comments. Hereditary hemochromatosis should be considered early in the evaluation of men of northern European descent.
Patients usually have no symptoms until iron
overload causes significant end-organ damage.
Phlebotomy can be an effective treatment for
this potentially fatal disease.6
Alcoholic liver disease
Risk factors. The degree of alcohol-related liver disease depends on a variety of factors,
including the volume and duration of alcohol
ingestion, the type of liver disease, genetics,
and the coexistence of viral hepatitis and obesity.
Alcohol-related liver disease can range
from simple fatty liver to alcoholic hepatitis
with or without cirrhosis. Cirrhosis develops
in only 20% to 30% of patients who consume
a substantial amount of alcohol, defined as
more than a decade of 60 g/day to 80 g/day
of alcohol in men and as little as 20 g/day in
women. (A standard drink, ie, a 12-ounce
beer, a 5-ounce glass of wine, or 1.5 ounces
of distilled spirits, contains 12 g of alcohol.)
Factors that potentiate alcohol’s harmful effects include female sex, chronic viral hepatitis (especially hepatitis C), obesity, hereditary hemochromatosis, and use of drugs such
as methotrexate (Trexall) and acetaminophen
(Tylenol).
Comments. Although cirrhosis affects fewer than one-third of long-term heavy drinkers,
early detection and treatment can potentially
reduce morbidity and prevent early death. Alcoholic liver disease should be suspected in
patients with elevated ALT and AST levels
(if the AST level is two to three times higher
than normal7) and with a history of excessive
alcohol use.
Studies
suggest that
fatty liver, due
to alcohol or
nonalcoholic
steatohepatitis,
is the major
cause of mildly
elevated
aminotransferases
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Table 2
Hepatotoxicity of selected drugs
Hepatobiliary
diseases and
several bone
conditions
can cause
a moderately
to markedly
elevated
alkaline
phosphatase
level
198 Hepatocellular abnormalities
Acetaminophen (Tylenol)—acute hepatitis
Allopurinol (Zyloprim)—granuloma
Azathioprine (Imuran)—veno-occlusive disease,
nodular regenerative hyperplasia
Diclofenac (Voltaren) and other nonsteroidal
anti-inflammatory drugs
Hydralazine (Apresoline)—granuloma
Isoniazid
Methotrexate—fibrosis
Methyldopa (Aldomet)
Nitrofurantoin (Furadantin, Macrobid)—
autoimmune-like disease
Quinidine—granuloma
Statins
Cholestatic abnormalities
Amoxicillin-clavulanate (Augmentin) and other
penicillin derivatives
Anabolic steroids
Captopril (Capoten)
Chlorpromazine (Thorazine)
Erythromycin estolate
Estrogens
Oral contraceptives
Phenytoin (Dilantin)—mononucleosis-like
syndrome
Carbamazepine (Tegretol)
Sulfa drugs
Drug-induced fatty liver
(with or without hepatocellular abnormalities)
Amiodarone (Cordarone)—phospholipidosis
Corticosteroids
Tetracycline
Valproic acid (Depakote)
Nonalcoholic fatty liver disease
Prevalence. Nonalcoholic fatty liver disease is a spectrum that ranges from simple steatosis to nonalcoholic steatohepatitis to cirrhosis. Its prevalence in the general US population
is about 25%, but is much higher in groups at
risk, such as patients with type 2 diabetes (50%
to 60%), and morbidly obese patients undergoing bariatric surgery (90% to 95%).
On the other hand, the prevalence of
the potentially progressive form of nonalcoholic fatty liver disease, ie, nonalcoholic
steatohepatitis, is estimated to be 3% to 5%.
Nonalcoholic fatty liver disease is perhaps the
most common cause of mildly elevated liver
enzymes in the United States.
Risk factors. The major risk factors for
nonalcoholic fatty liver disease are the components of the metabolic syndrome—ie, abdominal obesity, diabetes (insulin resistance),
hyperlipidemia, and hypertension—and the
use of certain medications (Table 2).
Comments. Nonalcoholic steatohepatitis
and steatonecrosis describe a potentially progressive form of nonalcoholic fatty liver disease. Although these disorders are histologically indistinguishable from alcohol-induced
liver disease, their mechanism is related to insulin resistance, abnormalities of lipid metabolism, increased hepatic lipid peroxidation,
activated fibrocytes, and abnormal patterns
of adipokine and cytokine production related
to visceral obesity. Results from a few natural
history studies suggest that simple steatosis has
a benign course, whereas nonalcoholic steatohepatitis can progress to cirrhosis in 10% to
20% of patients.8
Treatment of diabetes, obesity, hypertension, and hyperlipidemia has potential benefit
and should be undertaken regardless of liver
test abnormalities in any patient with underlying nonalcoholic fatty liver disease.
Autoimmune hepatitis
Prevalence. The prevalence of autoimmune hepatitis varies, depending on geographic location and on the extent of viral hepatitis
in the community. In Hong Kong, only 1% of
all people with chronic hepatitis have autoimmune hepatitis. By contrast, in Germany and
Austria, 34% and 62% of patients with chronic hepatitis may have autoimmune hepatitis.9
In North America, the prevalence of autoimmune hepatitis in patients with chronic liver
disease is estimated to be 11% to 23%, and the
incidence is about 0.68 per 100,000 individuals per year. In addition to underlying genetic
differences, detection bias can explain the
variability in prevalence rates.
Risk factors. Autoimmune hepatitis occurs predominantly in women and can be associated with other autoimmune disorders.
Comments. The diagnosis of autoimmune hepatitis is suggested by exclusion of
viral causes of chronic hepatitis, by pathologic
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Aragon and Younossi
findings, and by the presence of autoimmune
markers such as antinuclear antibody, smooth
muscle antibody, and liver-kidney microsomal
antibody. Hypergammaglobulinemia is present in most patients, and serum protein electrophoresis may be helpful as part of the initial
evaluation of autoimmune hepatitis.
Liver biopsy is usually needed to confirm
the diagnosis and to stage the extent of fibrosis. The International Autoimmune Hepatitis
Group Scoring System is based on clinical,
laboratory, and pathologic data and can be
very helpful in establishing the diagnosis.
Treatment of autoimmune hepatitis with
immunosuppression is effective. Most patients
may need long-term maintenance treatment.
Wilson disease
Prevalence. The estimated prevalence of
Wilson disease is 1 in 40,000 to 1 in 100,000.
It has been reported in most populations
worldwide.
Risk factors. Anyone under age 40 with
abnormal liver enzyme levels (including mild
elevations) should be evaluated for Wilson
disease, even in the absence of neurologic
or ocular findings. However, such routine
screening is rarely helpful in patients over
age 50. Genetic testing is of limited value
because of the large number of potential mutations of the ATP7B gene, the gene responsible for Wilson disease. However, if a a person is known to have Wilson disease, genetic
screening of family members is useful.
Comments. Effective therapy is available
(ie, d-penicillamine, trientine, zinc). For Wilson disease, alpha-1-antitrypsin deficiency,
and genetic hemochromatosis, establishing
the diagnosis is not only important to the individual patient; it also may prompt the screening of asymptomatic members of the proband’s
family.10–12
Alpha-1-antitrypsin deficiency
Prevalence. Alpha-1-antitrypsin deficiency is present in 1 of every 1,600 to 1,800 live
births.11
Risk factors. Patients with emphysema or
with a young sibling with liver failure should
undergo an investigation for alpha-1-antitrypsin deficiency, consisting of a measurement of
the alpha-1-antitrypsin level and an assess-
ment for the PiZZ genotype (the most severe
form, because homozygous for the abnormal Z
allele).
Comments. Although alpha-1-antitrypsin
deficiency is a common cause of liver disease
in the very young, it is important to remember
that a small number of these patients develop
end-stage liver disease in adulthood. Liver
transplantation is the only effective treatment
for end-stage liver disease associated with alpha-1-antitrypsin deficiency.
Primary biliary cirrhosis
Prevalence. In one study of urban-dwelling
women in northeast England, the prevalence
of primary biliary cirrhosis was estimated at
0.10%.13
Risk factors. Like autoimmune hepatitis,
primary biliary cirrhosis mainly affects women
and can be associated with other autoimmune
disorders.
Comments. A cholestatic pattern of injury
is predominant in primary biliary cirrhosis.
Treatment of primary biliary cirrhosis with
the cytoprotective agent ursodeoxycholic acid
improves liver enzyme levels, may lead to histologic improvement and increased survival,
and may also delay the need for liver trans- Extensive
plantation.9,13
workup
Drug- and toxin-related liver diseases
Nonsteroidal anti-inflammatory drugs and
penicillin-derived antibiotics are the drugs
that most commonly cause abnormal serum
liver enzyme levels. The mechanisms of druginduced liver disease include induction of hepatic enzymes (antiepileptic drugs), allergic
reactions, autoimmunity (nitrofurantoin [Furadantin, Macrobid]), idiosyncratic reactions,
and veno-occlusive injury.14 Drugs that are potentially hepatotoxic are listed in Table 2 and
are classified as causing hepatocellular damage, cholestatic damage, or steatosis.
of an isolated
GGT elevation
in an
apparently
healthy
patient is not
warranted
■■ MILD ENZYME ELEVATIONS
AS INDICATORS OF SPECIFIC DISEASES
Mildly elevated liver enzymes are common
and potentially important, yet very few welldesigned prospective studies have addressed
the issue of what should be done once they
are identified. Most current data are from
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small retrospective studies that lack accurate
information on the important causes of liver
diseases such as hepatitis C and nonalcoholic
steatohepatitis.
Despite these shortcomings, the literature
delineates the three patterns of mild liver enzyme elevations discussed earlier: hepatocellular
injury pattern (elevated ALT or AST), cholestatic pattern (elevated alkaline phosphatase or
GGT, or both), and mixed pattern (elevation of
ALT, AST, and alkaline phosphatase). The following paragraphs focus on the causes of elevation of specific liver enzymes.
■■ Aminotransferase elevation
An AST level
more than
twice the ALT
suggests the
damage is due
to alcohol
Causes
Aminotransferases are commonly used markers of hepatocyte injury. AST is present in
blood cells and many tissues, including liver,
muscle, brain, pancreas, and lung. ALT is a
cytosolic enzyme found primarily in hepatocytes, making it a more specific indicator of
liver disease.
Acute viral hepatitis, toxins, and liver
ischemia can markedly raise serum aminotransferase levels (often into the thousands of
units per liter). On the other hand, these enzymes are only mildly elevated (< 300 U/L) in
nonalcoholic steatohepatitis, chronic hepatitis, cholestatic liver conditions, drug-induced
hepatotoxicity, and liver tumors.
Because AST is a mitochondrial enzyme
and is affected by alcohol ingestion, an AST
level more than twice that of the ALT suggests
hepatic damage due to alcohol.
Of note, aminotransferase elevation can
also be due to nonhepatic causes. For example, muscle necrosis can result in mild elevation of these enzymes, especially AST, and an
elevated creatine kinase can help confirm that
the source is muscle tissue.
Undiagnosed celiac disease has been associated with abnormal liver enzyme levels
when all other causes have been ruled out,
but the mechanism is not yet understood. In
this situation, ALT and AST levels typically
return to normal with a gluten-free diet.15
Studies of mild aminotransferase elevations
Only a few studies have documented the results of a thorough evaluation of patients with
200 mildly elevated aminotransferase levels:
Hultcrantz et al1 performed a full evaluation, including liver biopsy, in 149 consecutive
patients with chronic, asymptomatic, mild elevations of AST or ALT. Of these patients,
63% had “fatty liver,” 20% had “chronic hepatitis,” and 17% had miscellaneous diagnoses.
Whether patients in the “chronic hepatitis”
group had hepatitis C was not determined because serologic testing was not available at the
time.
Friedman et al16 studied 100 healthy blood
donors with elevated ALT levels and found
that in 33% of patients the elevation occurred
once, in 36% it was intermittent, and in 28%
it was persistent. In this series, 45% of patients
had no diagnosis, 22% were obese (presumed
to have nonalcoholic steatohepatitis), 5%
had alcoholic liver disease, 3% had “resolving
hepatitis,” 1% had hemochromatosis, and 1%
had “cytomegalovirus hepatitis.”16 Although
the patients underwent a complete history,
physical examination, and serologic testing,
liver biopsy was not done to confirm the clinical diagnosis.
Hay et al17 described 47 patients with
chronically elevated aminotransferases (three
to eight times higher than normal levels) who
underwent full evaluation and liver biopsy and
who had no clinical symptoms of alcoholic, viral, or drug-induced liver disease. A diagnosis
of steatohepatitis was given in 10 patients, another 34 were diagnosed with “chronic hepatitis,” and 3 had miscellaneous diagnoses. Of patients with chronic hepatitis, 16 had evidence
of cirrhosis on biopsy, and 18 tested positive for
at least one autoimmune marker (antinuclear
antibody or smooth muscle antibody).
Daniel et al18 performed biopsy in 81 of
1,124 asymptomatic and symptomatic patients with chronically elevated aminotransferases in whom a cause was not identified via
noninvasive studies. Liver biopsy showed that
67 (83%) of the 81 patients had steatosis or
steatohepatitis, while 8 (10%) had normal
histologic findings. Of note, 6 patients had
underlying fibrosis or cirrhosis and some degree of fatty infiltration.
Together, these studies suggest that fatty
liver, resulting either from alcohol use or from
nonalcoholic fatty liver disease, is the major
cause of mildly elevated aminotransferases.
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Two major drawbacks of the earlier studies
include the lack of data on the hepatitis C serologic status of patients with the diagnosis of
“chronic hepatitis” and the lack of a uniform
approach to the pathologic diagnosis of nonalcoholic steatohepatitis. With serologic testing for hepatitis C virus infection now widely
available, it is possible that a substantial portion of patients with “chronic hepatitis“ can
further be classified as having chronic hepatitis C infection.
Workup of aminotransferase elevations
Figure 1 shows an algorithm for evaluating patients with elevated aminotransferase levels
on an initial examination. The first step is
to confirm the abnormality by repeating the
blood test. If an enzyme elevation is confirmed,
further investigation is warranted. A directed
history and physical examination can provide
crucial clues in the preliminary workup. The
history may disclose risk factors for:
• Viral hepatitis (intravenous drug use, intranasal cocaine use, native of an endemic
area of the world, unsafe sexual activity,
blood product transfusions)
• Nonalcoholic fatty liver disease (components of the metabolic syndrome, including visceral obesity)
• Alcoholic liver disease (smaller amounts
are needed to cause liver disease in women)
• Medication exposure (prescription, overthe-counter, and herbal medications)
• Genetic liver disorders (family history of
liver disease)
• Possible coexisting disease (diabetes and
obesity in nonalcoholic steatohepatitis,
neurologic disorders in Wilson disease,
emphysema in alpha-1-antitrypsin deficiency, thyroid disease in autoimmune
hepatitis and primary biliary cirrhosis, and
diabetes and impotence in genetic hemochromatosis).
Although the physical signs of chronic
liver disease (eg, spider angiomata, palmar
erythema, caput medusae, and gynecomastia) are nonspecific and are usually observed
in advanced liver disease, some physical
findings suggest potential causes (eg, KayserFleischer rings on slit-lamp examination for
Wilson disease, hypertrophy of the second
and third metacarpophalangeal joints for
hemochromatosis). Iron studies for middleaged men, autoimmune markers for women,
and screening for Wilson disease in young
patients are helpful when the clinical information points to one of these entities as a
potential diagnosis.
If medication or alcohol is a suspected cause,
aminotransferase levels should be repeated after 6 to 8 weeks of abstinence. If nonalcoholic
steatohepatitis is suspected, testing should be
repeated after treating the potential risk factor
(eg, obesity, diabetes, hyperlipidemia), but the
levels may remain elevated for a period of time.
An imaging study (ultrasonography, computed
tomography, or magnetic resonance imaging)
may be helpful; eg, abdominal ultrasonography
may show increased hepatic echogenicity, suggesting increased fatty infiltration, in addition
to excluding most hepatic tumors.
If the clinical data obtained from the history or physical examination raise clinical suspicion for a particular disease, a disease-specific marker (figure 1 and figure 2) can further
support the potential diagnosis. Note that liver biopsy can help establish the diagnosis for
many liver disorders and is the best method
currently available to establish cirrhosis, with
important prognostic implications.19
If the history and physical do not suggest a specific condition, serologic testing for
hepatitis C should be done. If negative, other
testing can be helpful (iron studies in men,
autoimmune markers in women, ceruloplasmin and slit-lamp examination in young patients). If the preliminary workup remains
negative and the aminotransferase levels remain elevated for 6 months (ie, chronic elevation), liver biopsy may establish the diagnosis. Features in the biopsy specimens may
further confirm the diagnosis: eg, globules
positive on periodic acid-Schiff testing in
alpha-1-antitrypsin deficiency; hepatic iron
index for hemochromatosis; hepatic copper
content for Wilson disease.
If a drug
or alcohol is
the suspected
cause, retest
AST and ALT
after 6 to 8
weeks of
abstinence
■■ Alkaline phosphatase elevation
Causes
Alkaline phosphatase is active in many organs, mainly the liver and bones, but is also
found in the small bowel, kidneys, and placenta. Diseases of the hepatobiliary system
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Elevated alanine or aspartate aminotransferase
History and physical examination
Retest to confirm elevation
Normal
Abnormal
Test for hepatitis C
antibody if at risk
Disease suspected
(risk factors present)
+
Hepatitis C virus
RNA
+
Chronic
hepatitis C
Nonalcoholic fatty
liver disease
Autoimmune
hepatitis
Treat underlying risk Test positive for
factors
antinuclear antibody, anti-smoothmuscle antibody
Wilson disease
Hemochromatosis
Tests:
Ceruloplasmin
Tests:
Ferritin
24-hour urine
Percent iron
saturation
Slit-lamp test for
Kayser-Fleischer
rings
HFE mutation
Viral hepatitis
Alcohol- or
drug-related
Test for hepatitis
C virus, hepatitis
B surface antigen
Recheck after
6-8 weeks of
abstinence
+
Hepatitis C virus RNA or
hepatitis B virus DNA
Abnormal
Normal
Consider liver biopsy
Follow-up
figure 1. Algorithm for the evaluation of elevated aminotransferase levels. Black arrows indicate the
diagnostic pathway, and red arrows indicate the steps in staging the liver disease.
can cause moderate to marked elevations
of alkaline phosphatase. Conditions with
bone involvement, such as Paget disease of
the bone, sarcoma, metastatic disease, hyperparathyroidism, and rickets, can raise alkaline phosphatase levels. Elevated GGT in
conjunction with elevated alkaline phosphatase usually points to hepatobiliary injury.
Clinically, isoenzyme fractionation of alkaline phosphatase may help distinguish the
source of the elevation, but this is often not
needed if the GGT is also elevated.
Hepatobiliary causes of alkaline phosphatase elevation can be divided into four categories:
• Chronic inflammation involving the bile
ducts (eg, as in primary biliary cirrhosis
202 and primary sclerosing cholangitis)
• Infiltrative process (eg, neoplasm, tuberculosis, sarcoidosis)
• Cholestatic disorders (eg, drug hepatotoxicity)
• Biliary obstruction (eg, in neoplasia or
cholelithiasis).
Only a few studies have investigated the
significance of a mild, isolated elevation of alkaline phosphatase. Lieberman and Phillips20
evaluated 87 patients and found that the abnormality resolved completely in less than 3
months in 28 patients, and resolved in 3 to 12
months in another 17 patients. Of the other
42 patients, 24 did not undergo further evaluation because they had significant coexisting
disease. Of the remaining 18 patients, 5 had
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Elevated alkaline phosphatase
History and physical examination
Confirm and identify hepatobiliary source,
check gamma-glutamyl transferase to exclude
alcohol- or drug-related hepatitis and biliary
discomfort
Consider magnetic resonance
cholangiopancreatography
Consider
ultrasonography
iliary
B
dilation
Consider expert consultation
and endoscopic retrograde
cholangiopancreatography
Abnormal
Obstruction
Treat underlying
cause of obstruction
Disease suspected
if risk factors present
Alkaline phosphatase still
elevated at 6 months
Viral hepatitis
Primary sclerosing
cholangitis
Test for hepatitis C virus,
hepatitis B surface antigen
(for mixed pattern of injury)
Cholangiopancreatography
(magnetic resonance or endoscopic retrograde)
Primary biliary
cirrhosis
Test for antimitochondrial antibody
Drug-related
Recheck after
6-8 months of
abstinence
Abnormal
Normal
Consider liver biopsy
Follow-up
figure 2. Algorithm for the evaluation of elevated alkaline phosphatase levels. Black arrows indicate the
diagnostic pathway, and red arrows indicate the steps in staging the liver disease.
phenytoin-related hepatotoxicity, 3 had congestive heart failure, 3 had metabolic bone
disease, 2 had hepatobiliary disease, and 1 had
metastatic bone disease; in 4 patients, no explanation was determined. Follow-up was 1.5
to 3 years.
Workup of alkaline phosphatase elevation
An isolated elevated alkaline phosphatase
level should always be confirmed and a hepatic origin suspected if the GGT level is also
elevated (Figure 2).
A history of recent drug exposure usually
points to drug hepatotoxicity as the source
of this abnormality. Similarly, other informa-
tion from the history can point to a potential
underlying pathologic process causing the
rise in alkaline phosphatase. For example, a
history of ulcerative colitis suggests primary
sclerosing cholangitis, and a history of previous cancer or sarcoidosis suggests liver involvement.
As part of the initial evaluation, an imaging study (eg, ultrasonography) can exclude
biliary obstruction or suggest an infiltrative
process.
If a drug is the suspected cause, the alkaline phosphatase level should be repeated
after the patient has abstained from the drug
for 6 to 8 weeks. If the initial examination
CLEVEL A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 7 • N U M B E R 3 M A R C H 2 0 1 0 203
mildly Elevated liver enzymes
suggests a specific disease, disease-specific
markers (eg, antimitochondrial antibody for
primary biliary cirrhosis, or viral serology)
can confirm the suspected diagnosis. If the
disease-specific markers are negative and the
alkaline phosphatase level does not return to
normal, further studies should be considered,
including liver biopsy and endoscopic retrograde cholangiopancreatography or magnetic
resonance cholangiopancreatography. Given
the invasive nature of biopsy and pancreatography, an expert consultation should be done
before ordering these tests.
■■ GGT elevation
GGT is a membrane enzyme that is a marker of
hepatobiliary disease. Elevations usually parallel
the elevation of alkaline phosphatase, confirming a hepatic source for the latter. GGT is the
most sensitive marker of biliary tract disease
but is not very specific. Alcohol and drugs (eg,
phenytoin, pheno­barbital) induce GGT. In one
study,21 GGT was elevated in 52% of patients
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ADDRESS: Zobair M. Younossi, MD, MPH, Center for Liver Diseases, Inova
Fairfax Hospital, 3300 Gallows Road, Falls Church, VA 22042; e-mail zobair.
[email protected].
CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 77 • N U M B E R 3 M A R C H 2 0 1 0